A review of the molecular mechanisms of hyperglycemia‐induced free radical generation leading to oxidative stress

Abstract

The prevalence of diabetes is growing worldwide with an increasing morbidity and mortality associated with the development of diabetes complications. Free radical production is a normal biological process that is strictly controlled and has been shown to be important in normal cellular homeostasis, and in the bodies response to pathogens. However, there are several mechanisms leading to excessive free radical production that overcome the normal protective quenching mechanisms. Studies have shown that many of the diabetes complications result from excessive free radical generation and oxidative stress, and it has been shown that chronic hyperglycemia is a potent inducer for free radical production, generated through several pathways and triggering multiple molecular mechanisms. An understanding of these processes may help us to improving our preventive or therapeutic strategies. In this review, the major molecular pathways involved in free radical generation induced by hyperglycemia are described.

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“…At the same time, as one of the results of the disordered lipid metabolism, the increased ROS could be observed in T2DM patients, leading to the occurrence of oxidative stress (Huang et al, 2011). Hyperglycemia can also induce oxidative stress through several mechanisms, including glucose autooxidation, glycosylation end product formation, and the activation of alcohol pathway (Han, Zhang, Wang, & Zhang, 2013;Samadder et al, 2011;Yaribeygi & Atkin, 2019). Therefore, the role of oxidative stress cannot also be underestimated in the pathogenesis of T2DM-induced NAFLD.…”

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“…Such mechanisms include the mitochondrial mechanism, dysfunction of cellular antioxidative defense system (ADS), glucose autoxidation, lipid peroxidation, and activation of free-radical generator enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, xanithine oxidase, cytochrome P450 (CYP450), myeloperoxidase, and uncoupled endothe- Oxidative Medicine and Cellular Longevity free radical formation. These include accelerated electron disposition into the electron transport chain of the mitochondria through influx electron donation aided by complexes I, III, and IV; escape of electrons; repression of the function of the mitochondria antioxidative defense system (ADS); and alteration of mitochondrial DNA [87]. The chief role of the mitochondria in the cell is energy generation (ATP) through oxidative phosphorylation.…”

“…The presence of manganese-dependent superoxide dismutase (MnSOD) in the mitochondria transforms O 2 to H 2 O 2 and O 2 . Research findings have implicated the hyperglycemic state to be one of the reasons why there is a diminished level in mitochondria ADS expression in addition to a weakened buffering potential [87,88,92]. Mutation in mDNA influenced by hyperglycemia promotes the decline in the level of MnSOD, peroxiredoxins (PRX), thioredoxin (TRX), and 8-hydroxydeoxyguanosine [93].…”

“…In addition, lower levels of erythrocytes, hepatic cells, lymphocytes, and vascular endothelial cells are predominant in diabetic subjects. All these 5 Oxidative Medicine and Cellular Longevity diminished levels are the resultant effects of an upsurge in the activity of free radicals [87,[96][97][98]. Several mechanisms have been highlighted to be the likely causes of ADS-induced diabetes.…”

“…Its absence/shortage could trigger an aberration in ABS expression. Antioxidative enzyme glycation and inactivation is another mode by which ADS is altered in diabetes [87,94]. According to Kakkar et al [100], a deficiency in insulin promotes the activation of fatty acyl-coenzyme A oxidase which results in excessive generation of H 2 O 2 .…”